Imaging of biologically targeted markers is gaining increased attention for its potential to provide early disease detection, improved individualized risk stratification and monitoring of medical therapies. The molecular tracer 123I-metaiodobenzylguanidine (123I-MIBG) is an analog of norepinephrine which provides a noninvasive approach for imaging the sympathetic innervations of the heart. The overall goal of this project is to develop clinical software tools for quantification of 123I-MIBG molecular imaging of heart failure to facilitate clinical translation of this important imaging technology to routine clinical practice. The specific aims of this project are to: 1) develop software methods for improved quantification of clinical 123I-MIBG SPECT imaging of heart failure patients, 2) develop a novel software method for accurate automated quantification of HMR and WR from planar views projected from the reconstructed 123I-MIBG SPECT images of Aim 1, and 3) clinical validation of the software tools developed in Aims 1 and 2 using retrospective analysis of image data and clinical outcomes from Phase III clinical trials of cardiac 123I-MIBG imaging. The results of recently completed Phase III trials have demonstrated that 123I-MIBG cardiac imaging can identify a subpopulation of heart failure patients with low 2-year risk of fatal cardiac events and the potential to define patients with increased likelihood of heart failure progression, ventricular arrhythmias, or cardiac death. These promising results are based on simple global quantitative measures of cardiac 123I-MIBG uptake, such as the heart-to-mediastinum ratio (HMR) and washout rate (WR), using planar radionuclide imaging. However, recent data has shown that the lack of standardized acquisition and processing protocols for planar imaging has limited the applicability of 123I-MIBG for widespread use. Moreover, single photon emission computed tomography (SPECT) imaging has the potential for more accurate quantification of 123I-MIBG uptake and retention. Unfortunately SPECT quantification has been hampered by the physical properties of imaging 123I labeled tracers, and the characteristically rapid sympathetic neuronal washout and low cardiac retention of 123I-MIBG in heart failure patients. The proposed project will address these limitations by developing a comprehensive approach for improved quantification of 123I-MIBG SPECT, including the application of recent advances in SPECT iterative reconstruction with corrections for photon attenuation, scatter and septal penetration and detector response modeling and novel methods for automated segmentation of the left ventricle (LV) in emission images. We anticipate that the successful outcome of the proposed project will provide automated quantification methods, software tools and validation data that will be extremely useful in future efforts to define guidelines and standards for the acquisition and processing of 123I-MIBG molecular imaging of heart failure. PUBLIC HEALTH RELEVANCE: The use of molecular imaging for management of heart failure patients is a recent advance that enables more individualized patient care, improved assessment of risk for adverse events, and can potentially reduce the healthcare costs associated with heart failure. This proposal will develop imaging software necessary for advancing molecular imaging technology to the clinic practice and facilitate wider clinical adoption of this promising advance in the care of heart failure patients.